Improving Reporter Gene Assay Methodology for Evaluating the Ability of Compounds to Restore P53 Activity.

Tumor suppressor protein P53 induces cycle arrest and apoptosis by mediating the transcriptional expression of its target genes. Mutations causing conformational abnormalities and post-translational modifications that promote degradation are the main reasons for the loss of P53 function in tumor cells. Reporter gene assays that can scientifically reflect the biological function can help discover the mechanism and therapeutic strategies that restore P53 function. In the reporter gene system of this work, tetracycline-inducible expression of wild-type P53 was used to provide a fully activated state as a 100% activity reference for the objective measurement of biological function. It was confirmed by RT-qPCR, cell viability assay, immunofluorescence, and Western blot analysis that the above-mentioned reporter gene system could correctly reflect the differences in biological activity between the wild-type and mutants. After that, the system was tentatively used for related mechanism research and compound activity evaluation. Through the tetracycline-induced co-expression of wild-type P53 and mutant P53 in exact proportion, it was observed that the response modes of typical transcriptional response elements (TREs) to dominant negative P53 mutation effect were not exactly the same. Compared to the relative multiple-to-solvent control, the activity percentage relative to the 100% activity reference of wild-type P53 can better reflect the actual influence of the so-called P53 mutant reactivator. Similarly, relative to the 100% activity reference, it can objectively reflect the biological effects caused by the inhibitor of P53 negative factors, such as MDM2. In conclusion, this study provides a 100% activity reference and a reliable calculation model for relevant basic research and drug development.

Update on histone deacetylase inhibitors in peripheral T-cell lymphoma (PTCL).

Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.

Discovery of a novel, liver-targeted thyroid hormone receptor-ß agonist, CS271011, in the treatment of lipid metabolism disorders.

Introduction: Thyroid hormone receptor ß (THR-ß) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-ß agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo. Methods: We conducted luciferase reporter gene assays to assess the activation of THR-ß and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011. Results: Compared with MGL-3196, CS271011 showed higher THR-ß activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes. Conclusions: CS271011 is a potent and liver-targeted THR-ß agonist for treating lipid metabolism disorders.

Spatial Transcriptomics Analysis Reveals that CCL17 and CCL22 are Robust Indicators of a Suppressive Immune Environment in Angioimmunoblastic T Cell Lymphoma (AITL).

BACKGROUND: T cell lymphoma is a complex and highly aggressive clinicopathological entity with a poor outcome. The angioimmunoblastic T-cell lymphoma (AITL) tumor immune microenvironment is poorly investigated. METHODS: Here, to the best of our knowledge, spatial transcriptomics was applied for the first time to study AITL. RESULTS: Using this method, we observed that AITL was surrounded by cells bearing immune-suppressive markers. CCL17 and CCL22, the dominant ligands for CCR4, were up-regulated, while the expression of natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) markers decreased. Colocalization of Treg cells with the CD4+ TFH-GC region was also deduced from the bioinformatic analysis. The results obtained with spatial transcriptomics confirm that AITL has a suppressive immune environment. Chemotherapy based on the CHOP regimen (cyclophosphamide, doxorubicin, vincristine plus prednisone) induced complete remission (CR) in this AITL patient. However, the duration of remission (DoR) remains a concern. CONCLUSIONS: This study demonstrates that AITL has an immune suppressive environment and suggests that anti-CCR4 therapy could be a promising treatment for this lethal disease.

[The experiences of caregivers caring for children with cord blood transplantation].

BACKGROUND: Advancing technology has greatly increased cord blood transplantation (CBT) success rates. However, transplant patient caregivers may encounter a great deal of stress related to knowledge deficits with regard to post-transplant care and lack of relevant care experience. Existing studies for CBT primarily focus on investigating the transplant process and survival rate. Studies on the experience of caregivers caring for CBT children are extremely scarce. It is important for future studies to explore the care experiences of CBT caregivers. PURPOSE: This study explored the experiences of primary caregivers responsible to care for pediatric patients after CBT. METHODS: Researchers conducted a phenomenological study of lived experiences using qualitative interviews that were in-depth, face-to-face, and semi-structured. RESULTS: Colaizzi analysis identified three themes, as follows: (1) emotional transition; (2) bearing indescribable of stress; (3) searching for management in meaningful resolutions. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Study results can provide valuable insights and information to healthcare providers developing preparatory educational programs for caregivers of discharged CBT patients. Findings can help alleviate care stress and anxiety in caregivers and nurses.

Effects of a Clinically Indicated Peripheral Intravenous Replacement on Indwelling Time and Complications of Peripheral Intravenous Catheters in Pediatric Patients: A Randomized Controlled Trial.

Peripheral intravenous catheters (PVCs) are common treatment modalities for pediatric patients, and may cause infection, infiltration, occlusion, and phlebitis. The purpose of this study was to evaluate the effect of a clinically indicated peripheral intravenous replacement (CIPIR) on PVC indwelling time and complication rates in pediatric patients. This study used a randomized, pre- and post-repeated measures design. A total of 283 participants were randomly assigned to an experimental group (n = 140) and a control group (n = 143). The experimental group received CIPIR and the control group received usual care with routine PVC replacement every three days. The insert sites of PVC were assessed every day until the signs of infiltration, occlusion, or phlebitis were presented. Patients in the experimental group had significantly longer PVC indwelling times compared to those in the control group (t = -18.447, p < 0.001). No significant differences were noted between groups in infiltration (χ2 = 2.193, p = 0.139), occlusion (χ2 = 0.498, p = 0.481), or phlebitis (χ2 = 3.865, p = 0.050). CIPIR can prolong the PVC indwelling time in pediatric patients with no increase in the rate of adverse events.

Examining Response to Negative Life Events Through Fitness Tracker Data.

Negative life events, such as the death of a loved one, are an unavoidable part of life. These events can be overwhelmingly stressful and may lead to the development of mental health disorders. To mitigate these adverse developments, prior literature has utilized measures of psychological responses to negative life events to better understand their effects on mental health. However, psychological changes represent only one aspect of an individual's potential response. We posit measuring additional dimensions of health, such as physical health, may also be beneficial, as physical health itself may be affected by negative life events and measuring its response could provide context to changes in mental health. Therefore, the primary aim of this work was to quantify how an individual's physical health changes in response to negative life events by testing for deviations in their physiological and behavioral state (PB-state). After capturing post-event, PB-state responses, our second aim sought to contextualize changes within known factors of psychological response to negative life events, namely coping strategies. To do so, we utilized a cohort of professionals across the United States monitored for 1 year and who experienced a negative life event while under observation. Garmin Vivosmart-3 devices provided a multidimensional representation of one's PB-state by collecting measures of resting heart rate, physical activity, and sleep. To test for deviations in PB-state following negative life events, One-Class Support Vector Machines were trained on a window of time prior to the event, which established a PB-state baseline. The model then evaluated participant's PB-state on the day of the life event and each day that followed, assigning each day a level of deviance relative to the participant's baseline. Resulting response curves were then examined in association with the use of various coping strategies using Bayesian gamma-hurdle regression models. The results from our objectives suggest that physical determinants of health also deviate in response to negative life events and that these deviations can be mitigated through different coping strategies. Taken together, these observations stress the need to examine physical determinants of health alongside psychological determinants when investigating the effects of negative life events.

Efficacy and Treatment-Related Adverse Events of Romidepsin in PTCL Clinical Studies: A Systematic Review and Meta-Analysis.

Background: Peripheral T-cell lymphoma (PTCL) is an extensive class of biologically and clinically heterogeneous diseases with dismal outcomes. The histone deacetylase inhibitor (HDACi) romidepsin was approved for relapsed and refractory (R/R-PTCL) in 2011. This meta-analysis was performed to assess the efficacy and safety of romidepsin in PTCL. Methods: We searched for articles on the HDAC inhibitor romidepsin in the treatment of PTCL in Embase, Web of Science, and PubMed. The methodology is further detailed in PROSPERO (CRD42020213651, CRD42020213553). The 2-year overall survival (OS), 2-year progression-free survival (PFS), and their corresponding to 95% confidence intervals (CIs) were measured. Besides, corresponding 95% CIs were pooled for the complete response (CR), partial response (PR), duration of response (DoR), and risk of adverse events (AEs). Results: Eleven studies containing 388 patients were incorporated into the quantitative synthesis, of which R/R-PTCL patients were the dominant portion, accounting for 94.3% (366/388). For all studies, the CR rate was 20% (95% CI, 13-27%, random effects model), and the PR rate was 18% (95% CI, 12-25%, random effects model). The 2-year OS was 48% (95% CI, 38-59%, fixed effects model), and the 2-year PFS was 17% (95% CI, 13-21%, fixed effects model). There were no significant differences between romidepsin monotherapy and romidepsin plus additional drugs. Hematological toxicities, such as lymphopenia and granulocytopenia, remained the most continually happening grade 3 or higher AEs, accounting for 46 and 28%, respectively. None of the studies reported any drug-related mortality. Conclusions: Considering that most of the included patients had R/R-PTCL, the addition of romidepsin significantly enhance the efficacy. And AEs were tolerable as the grade 3/4 AEs in romidepsin monotherapy was 7% (95% CI, 6-8%). It is imperative to further expand the first-line application of romidepsin and carry out personalized therapy based on epigenomics, which will improve the survival of PTCL patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020213651 and https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020213553.

Mineralization and nutrient release pattern of vermicast-sawdust mixed media with or without addition of Trichoderma viride.

A combination of vermicast and sawdust mixed medium is commonly used in horticulture, but the added benefit of microbial inoculation and mechanism of nutrient availability are unknown. This study was done to determine nutrient mineralization and nutrient release patterns of different combinations or a mix of vermicast-sawdust growing media amended with or without Trichoderma viride (105 spores/g). The mixed-media treatments were (1) 80% vermicast+20% sawdust; (2) 60% vermicast+40% sawdust; (3) 40% vermicast+60% sawdust; (4) 20% vermicast+80% sawdust; and (5) sawdust alone (control). Total dissolved solids, electric conductivity and salinity increased with each sampling time following submergence in deionized. Nutrients released from media without T. viride were significantly higher than the corresponding media with added T. viride. Overall, the starting total nitrogen of the different media did not change during the incubation period, but nitrate-nitrogen was reduced to a negligible amount by the end of day 30 of incubation. A repeated measures analysis showed a significant effect of Time*T. viride*Treatment on total dissolved solids. Redundancy analysis demonstrated a positive and strong association between media composed of ≥40% vermicast and ≤60% sawdust with or without T. viride and mineral nutrients released, electrical conductivity, total dissolved solids and salinity. These findings suggest that fast-growing plants may benefit from 40% to 60% vermicast added to 40% to 60% sawdust without T. viride while slow-growing plants can benefit from the same mixed medium combined with the addition of T. viride. Further investigation is underway to assess microbial dynamics in the mixed media and their influence on plant growth.

CXCL1 Clone Evolution Induced by the HDAC Inhibitor Belinostat Might Be a Favorable Prognostic Indicator in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its lack of treatment options. Patients with TNBC frequently develop resistance to chemotherapy. As epigenetic-based antineoplastic drugs, histone deacetylase inhibitors (HDACis) have achieved particular efficacy in lymphoma but are less efficacious in solid tumors, and the resistance mechanism remains poorly understood. In this study, the GSE129944 microarray dataset from the Gene Expression Omnibus database was downloaded, and fold changes at the transcriptome level of a TNBC line (MDA-MB-231) after treatment with belinostat were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the critical biological processes. Construction and analysis of the protein-protein interaction (PPI) network were performed to screen candidate genes related to cancer prognosis. A total of 465 DEGs were identified, including 240 downregulated and 225 upregulated genes. The cytokine-cytokine receptor pathway was identified as being significantly changed. Furthermore, the expression of CXCL1 was implicated as a favorable factor in the overall survival of breast cancer patients. With in vitro approaches, we also showed that belinostat could induce the expression of CXCL1 in another 2 TNBC cell lines (BT-549 and HCC-1937). We speculate that belinostat-induced CXCL1 expression could be one of the results of the stress clone evolution of cells after HDACi treatment. These findings provide new insights into clone evolution during HDACi treatment, which might guide us to a novel perspective that various mutation-targeted treatments should be implemented during the whole treatment cycle.

Social network structure is predictive of health and wellness.

Social networks influence health-related behavior, such as obesity and smoking. While researchers have studied social networks as a driver for diffusion of influences and behavior, it is less understood how the structure or topology of the network, in itself, impacts an individual's health behavior and wellness state. In this paper, we investigate whether the structure or topology of a social network offers additional insight and predictability on an individual's health and wellness. We develop a method called the Network-Driven health predictor (NetCARE) that leverages features representative of social network structure. Using a large longitudinal data set of students enrolled in the NetHealth study at the University of Notre Dame, we show that the NetCARE method improves the overall prediction performance over the baseline models-that use demographics and physical attributes-by 38%, 65%, 55%, and 54% for the wellness states-stress, happiness, positive attitude, and self-assessed health-considered in this paper.